The present invention relates to a composition suitable both for the prevention of articular disorders and for the therapeutic treatment of articular diseases. Accordingly, the composition may take the form and exert the activity of a food or dietary supplement or of an actual medicament in the strict sense, depending upon the particular individuals in whom it is to be used and for reasons which will appear evident here below.
The most widespread articular disease is osteoarthrosis, a disease mainly affecting the hyaline cartilage and the subchondral bone with hypertrophy of the articular and periarticular tissues in the sites affected.
Osteoarthrosis sets in asymptomatically between the ages of twenty and thirty years, affecting both sexes with the same frequency, though the onset tends to be earlier in males. Around the age of forty, almost all subjects begin to present some pathological abnormality of the joints under conditions of mechanical stress, though only a relatively small number of such individuals present clear-cut symptoms.
The disease becomes universally widespread and manifest in the course of the sixth decade of life.
Osteoarthrosis is the pathological result of a complex system of mechanical, biological, biochemical and enzymatic reactions: practically every process of an infectious, metabolic, endocrine, neurological or traumatic nature capable of impairing the structure and function of the hyaline cartilage and surrounding tissues constitutes an aetiological factor for the disease.
Since the onset is asymptomatic, deceptive and gradual, treatment is generally resorted to only after onset of a clearly defined, persistent symptomatological picture, if not, indeed, in the presence of various degrees of disability and functional impairment mainly affecting the knees and hips.
The drugs of choice are aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) whose adverse side effects and gastric damaging capability are well known.
It is precisely these adverse effects that induce physicians to delay the use of these therapeutic agents until such time as the symptomatological picture is stably consolidated and the resulting functional limitations threaten to impair the work, social and relational activities of the individuals affected.
There is therefore a perceived need for a preventive/therapeutic agent which, as a result of its substantial lack of toxicity and side effects, can be safely used at the first manifestation of symptoms or even earlier, once the patient has reached the age when, on average, such symptoms tend to manifest themselves. The aims of such treatment are both to delay the onset of the symptomatological picture and to combat development of the disease therapeutically.
These dual objectivesxe2x80x94preventive and strictly therapeuticxe2x80x94are achieved by the composition to the present invention, which, as will be described in detail here below, consists of a new combination containing as its basic ingredients L-carnitine or a C2-C6 lower alkanoyl-L-carnitine and a glucosaminoglycan and/or glucosamino-glycan component.
This composition is characterised by an unexpected and surprising anti-inflammatory and cartilage-protecting activity. As a result of these properties the new composition can be usefully applied in the prevention and therapeutic treatment of inflammatory or degenerative articular disorders mainly related to a metabolic dysfunction of the articular tissues, whether of endogenous or exogenous origin, induced by traumas or drugs. The new composition can also be usefully employed in both the human and veterinary fields.
The use of carnitine for the prevention and cure of metabolic dysfunctions is well known. Carnitine and its alkanoyl derivatives have been shown to be useful in the treatment of myocardial ischaemia, angina pectoris, peripheral vascular disease and in the various forms of atherosclerosis.
These therapeutic activities of carnitine and its alkanoyl derivatives are related to the complex biochemical activity which these compounds are capable of exerting at cell and tissue level.
In addition to being essential for the beta-oxidation of fatty acids, carnitine plays an important antioxidant role, as demonstrated by its protective effect against hyperoxidation of the cell phospholipid membranes and against oxidative stress induced at myocardial or endothelial cell level. In particular, carnitine has been shown to be capable of intervening in carbohydrate metabolism and insulin secretion.
The metabolic role of carnitine and its alkanoyl derivatives appears, however, to be very extensive and has yet to be clarified in many of its aspects. Carnitine has been found to increase the formation of arachidonic acid from linoleic acid and, by this pathway, to play an important role in modulating inflammation.
In addition, carnitine inhibits the release of inflammatory eicosanoids by peritoneal macrophages. In particular, propionyl-L-carnitine has been shown to be capable of potentiating the effects of a cytoprotective prostaglandin such as prostacyclin.
There is no evidence of a direct effect of L-carnitine on chondrocytes and on the articular cartilage, nor on glucosamine metabolism.
There is extensive evidence, however, in the literature for the protective effect induced by proteoglycans.
As is known, proteoglycans are macromolecules produced by the chondrocytes which make up the articular cartilage. The mechanical properties of the cartilage and the functionality of the joint depend mainly on them.
Proteoglycans are formed from a central protein to which the glucosaminoglycan chains are bound. In the articular cartilages, glucosaminoglycans are represented mainly by chondroitin sulphate which is a disaccharide polymer formed from glucuronic acid and N-acetylgalactosamine sulphate.
According to whether the esterification with sulphuric acid is in position 4 or position 6 of the galactosamine, we have chondroitin-4-sulphate, which is present above all at birth and in children, or chondroitin-6-sulphate which is peculiar to adults.
With ageing, proteoglycan metabolism slows down and the levels of chondroitin sulphate diminish.
The same situation is encountered in arthrosis where an incomplete and defective biosynthesis of proteoglycans is detected. The proteoglycan aggregates in the molecular structure of the arthrotic articular cartilage are partly depolymerised and the collagen fibre is defiberized.
Glucosamines are indispensable for the biosynthesis of proteoglycans and also permit synthesis of galactosamine amino sugar necessary for the biosynthesis of glucosaminoglycans. As regards the action of glucosamines, it has been demonstrated that these are capable of stimulating repair of damaged cartilaginous tissue.
Glucosamine added to cultures of synovial fibroblasts also stimulates the incorporation of serine in chondroitin sulphate and in dermatan sulphate, preventing cortisone-induced chondrocyte damage in the rat and experimental arthrosis in the rabbit.
It is also known that the exogenous administration of glucosamine, even by the oral route, can improve arthrotic articular damage.
Whereas, on the one hand, glucosamines exert an important metabolic action at the level of the articular tissue degraded by arthrosis, glucosaminoglycans, such as chondroitin sulphate, are responsible for the mechanical and elastic properties of the articular cartilage owing to their ability to retain the water necessary for the elastic state of the cartilage itself.
It has been demonstrated that, in arthrotic situations, there is a loss of water on the part of the cartilage, which therefore becomes less elastic as a result of the reduction in chondroitin sulphate, probably due to the action of proteolytic enzymes by the chondrocytes.
The exogenous administration of chondroitin sulphate makes it possible to block these enzymes, such as elastase, which degrade the articular cartilage. In addition, the exogenous administration of chondroitin sulphate also exerts a stimulating action on proteoglycan biosynthesis. Clinical improvements in the therapy of arthrosis obtained with the use of chondroitin sulphate have been reported by numerous authors, and this therapy has been successfully combined with traditional therapy using non-steroidal anti-inflammatory drugs (NSAIDs), without, however, being advocated as an alternative to NSAIDs.
On the basis of the characteristics of the products described above, the possibility of an interaction between them was assessed by means of a series of tests performed on combinations of L-carnitine or its alkanoyl derivatives and glucosaminoglycans and/or their components. On the basis of the tests performed with these new combinations an unexpected and surprising protective effect was observed in different models of experimental inflammation, as a result of a synergic action between the components of the combinations which was thoroughly unpredictable on the basis of our existing pharmacological knowledge of L-carnitine and its alkanoyl derivatives or of the glucosaminoglycans and their components.
The composition of the present invention comprises a combination of the following components:
(a) L-carnitine or an alkanoyl-L-carnitine wherein the alkanoyl group is a straight or branched group, having 2-8, preferably 2-6, carbon atoms, or a pharmacologically acceptable salt thereof;
(b) a glucosaminoglycan and/or a constituent of glucosaminoglycan; and
(c) a pharmacologically acceptable excipient.
The weight-to-weight ratio of component (a) to component (b ) ranges from 1.1 to 1:100, and preferably from 1:1 to 1:10.
The glucosaminoglycan is selected from the group comprising a chondroitin sulphate, hyaluronic acid, dermatan sulphate, keratan sulphate and heparan sulphate. Preferably, the chondroitin sulphate is either chondroitin-4-sulphate or chondroitin-6-sulphate.
The glucosaminoglycan constituent is selected from the group comprising glucosamine, glucosamine sulphate, N-acetylglucosamine, galactosamine and N-acetylgalactosamine.
The glucosaminoglycan and the glucosaminoglycan constituent can be obtained from natural products such as cartilages and collagen.
The alkanoyl-L-carnitine is preferably selected from the group comprising acetyl-L-carnitine, propionyl-L-carnitine, butyryl-L-carnitine, valeryl-L-carnitine and isovaleryl-L-carnitine. Acetyl-L-carnitine and propionyl-L-carnitine are particularly preferred.
What is meant by pharmacologically acceptable salt of L-carnitine or alkanoyl-L-carnitine is any salt of these with an acid which does not give rise to unwanted toxic or side effects. These acids are well known to pharmacologists and experts in pharmacy.